Process and apparatus for forming a dry DNA transfer film, a transfer film product formed thereby and an analyzing process using same

ABSTRACT

Pivotable jigs or tables facilitate inversion or reciprocation of one or more well plates relative to a dry DNA transfer sheet to effect deposit of DNA gene solution as spaced spots on the surface of the transfer media sequentially to produce after drying of the DNA gene solution transfer of the dry DNA material from the spots by forcible impact or rubbing pressure through a printing mechanism of minute dry DNA dots onto a test substrate such as a glass plate for subsequent analysis optically via fluorescent labels to determine the presence or absence of mutations and a further identification of the mutation itself.

FIELD OF THE INVENTION

[0001] This invention relates to the creation of a DNA analyzing arrayby separating DNA into individual genes, replicating the same andsolubilizing DNA genes in a solution of tens, hundreds or thousands ofdistinct microscopic squares called “features” on a gene chip orsubstrate.

BACKGROUND OF THE INVENTION

[0002] Typically, the DNA is separated into individual genes andreplicated many times in a number of 96 well plates (an industrystandard) and minute pieces of DNA are positioned on an underlyingsubstrate such as a chip from the DNA genes solubilized in a solution.After forming the DNA wet array and drying the DNA, the completed arrayis bathed in a solution of two or more fluoresces labeled total genomictags, with the tags hybridizing to bind to a particular gene on thearray by causing the fluoresces to fluoresce and measuring the intensityof the signals, determinations may be made between the various features.

[0003] To date, the creation of such array is complicated, and whilearrays have envisioned in terms of several thousand features persubstrate area, such arrays are produced in terms of days rather thanminutes. Further, while the well plates can store the individual geneswithin respective wells, over time the machine forming the wet arraysrequires constant cleaning to deter contamination of the arrays. Oncecreated, such gene chips are useful in testing for dozens of geneticdiseases of different severity, and the test can be cheaply and quicklyeffected. Chips have been produced; however, significant energy isrequired to realize a practical chip.

[0004] Affymetrix, Inc. has recently disclosed an approach utilizing aglass slide as a substrate, about half the size of a postage stamp withthousands of distinct microscopic squares (features), each attesting fora specific DNA sequence. The features on the glass surface are coveredwith a compound containing chemical protecting groups that block furtherchemical reaction. Optically, collected protecting groups can beremoved. A thin mask is then pulled over the chip containing holes toallow light to strike specific features, with the other features on thechip remaining protected. Subsequently, the chip is washed with asolution containing one of four DNA components called nucleotides (A, C,G or T). The DNA component washed solution binds only to the unprotectedfeatures. Each incoming nucleotide carries its own protecting group sothat the washed features are reprotected. Sequentially, a new mask withdifferent pattern of holes and optical (light) impingement removes theprotecting groups at the different pattern of holes associated with asecond group of features. In a multi-cycle process, chains of preciselyordered nucleotides are built onto each feature.

[0005] As may be appreciated, genes are made of two strands of DNAnucleotides of a specific order, bound to each other like the halves ofa zipper. Nucleotide binding is governed by certain relationships. Forinstance, the nucleotide T always binds with that of A, but never with Cor G, or with another T. Thus, a strand of nucleotides has a singlecomplimentary strand which will match it and bind exactly. Thus, a chip(or other substrate) containing nucleotide strands of a givencomposition can find specific mutations in a person's genes. Man hasapproximately 80,000 genes. Therefore, a DNA gene array of closelyspaced features or dots of microscopic size may be constituted by asmany as 400,000 dots on a single substrate and capable of carrying allDNA's for several persons, or one person in redundancy.

[0006] In the production of the DNA, the liquid DNA gene arrays, DNA isextracted typically from tissue cells grown in cultures, the DNA isfragmented into thousands of pieces which can be chemically labeled witha fluorescent compound. The pieces contain parts of genes or wholegenes. Thus, each feature of a chip contains a nucleotide strand of anormal or mutant section of a known gene. Thus, all possible mutationsof a gene can be detected by features on a single chip and all may betested simultaneously. By use of an optical scanner, the features on thechip can be read for fluorescent color and intensity. Featurescontaining fluorescently labeled DNA may provide signals fed to acomputer as input data, with that data being analyzed to provideinformation as to whether the person providing the genes carries one ormore mutations, and further the identification of the mutation itself.

[0007] It is therefore a primary object of the present invention toprovide a high throughput test system and components for ascertaininggenetic mutations enhanced by the dry, orderly world of computerhardware in contrast to the wet and messy world of living tissue and ofliquid DNA gene features applied to the slide by effecting a dry DNAtransfer film to create in turn, a dry DNA analyzing array of featuresor spots on such slide.

SUMMARY OF THE INVENTION

[0008] The present invention, in one form, is directed in part to animproved high throughput process of forming a dry DNA transfer media,such as film, paper, nitrocellulose, plastic or glass. For example, athin flexible, resilient film sized to the top surface of a generallyrigid well plate having such upper surface a plurality of closely spacedwells in column and line fashion within which are pre-placed separated,replicated DNA genes solubilized in a solution. The roughened surface ofthe thin flexible resilient film is sealed to the upper surface of thewell plate. Means are provided for effecting a rigid film plateassembly. The assembly may then be inverted to cause the DNA solutionunder gravity to physically, locally wet coat the roughened surface ofthe film, with the roughened surface causing the DNA gene solution tocling to the film while preventing the DNA gene solution from runningradially from one spot to another. The assembly is then reinverted toits initial position, and the DNA gene solution spotted film is removedslowly from the well plate. Upon drying, the DNA gene solution spotcoatings thereon form a dry DNA transfer film capable of physical andchemical dry transfer of DNA to a substrate.

[0009] The spot diameter or dimensions of the same and the spotconfiguration depend on the size and configuration of the wells withinthe well plate. The DNA gene solution spots may be air dried to speedthe process. A vacuum seal may be effected between the thin flexibleresilient film and the underlying well plate to momentarily fix the filmto the well plate prior to and while inverting the assembly. The thinflexible resilient film and well plate assembly may be secured in afixture or jig to facilitate rendering the assembly components fixedduring the inverting and reinverting steps and to maintain the sealbetween well plate and film during the initial liquid coating of theroughened surface of the film and to prevent the DNA gene solution fromrunning between the wells.

[0010] In another aspect, the present invention involves a dry DNAtransfer film as a product by the process described above.

[0011] In a further aspect of the invention, a dry form DNA analyzingprocess includes the following steps:

[0012] (a) sealing a flexible resilient film to the upper surface of arigid well plate having a plurality of spaced wells opening to the uppersurface and facing the film, the wells being prefilled with respective,separated, replicated DNA genes solubilized in a solution;

[0013] (b) forming a fixed, sealed assembly between the well plate andthe overlying thin flexible film;

[0014] (c) inverting the assembly to transfer DNA gene solution spots tothe facing surface of the film over localized areas of said film definedby respective wells;

[0015] (d) reinverting the assembly, removing the film and drying thetransferred DNA gene solution spots to thereby form a dry DNA genetransfer film;

[0016] (e) placing the dry DNA gene transfer film in a position facing aflat glass test substrate and applying force and movement such asmomentarily impacting the face of the DNA film on a face opposite thatbearing the spots at the spot locations to cause dry DNA to forciblylocally contact the substrate; whereby

[0017] portions of the dry DNA spots are transferred from the transferfilm to the test substrate by physical action and chemical attraction;and

[0018] (f) sequentially repeating the last step at different localizedDNA spot locations on the dry DNA transfer film to complete a dry DNAgene test dot array on the test substrate. The velocity of the impactdetermines the mass of the DNA transferred for the force applied.

[0019] The process preferably includes the further steps of bathing thedots with one or more total genomic tag fluorescences to hybridize thetag to a particular gene of the array, and optically scanning the arrayto identify dots containing fluorescently labeled DNA to determine theexistence of mutants or lack of same, and/or expression of known genesin the given cell line(s) or not. Alternatively, a rubbing forcedirected on the transfer media could transfer the dry DNA in a fashioninvolving a force applied tangentially to the test substrate withvelocity and force over a time period resulting in a mass of DNA beingtransferred.

[0020] Preferably, minute pieces of dry DNA are transferred from the DNAtransfer film spot to the substrate surface by feeding the film in afirst direction while moving a multi-pin print head across the film atright angles to the direction of feed of the film while impacting aselected print head pin against the film at the back of a preselectedDNA spot location to imprint a portion of a selected DNA spot onto thefacing surface of the test substrate.

[0021] The DNA transfer film may be supported on a print tractor or liketransport means for moving in a direction of the film's longitudinalaxis via perforations along the laterally offset edges of the film, withthe film underlying the print head and overlying a glass substrate andthe print head moving transversely across the top of the DNA transferfilm. The glass test substrate may be moved incrementally towards andaway from the film, cyclically timed to the movement of one or moreprint head pins such that the substrate is immediately adjacent to thetop surface of the DNA transfer film at the moment of print head pinimpact with the opposite surface of the DNA transfer film to thatcarrying the dry DNA spots.

BRIEF DESCRIPTION OF THE DRAWING

[0022]FIG. 1 is a schematic perspective view of a standard well platecovered by a DNA transfer film forming an invertible film/well assemblyforming key components of the preferred embodiment of the invention.

[0023]FIG. 2 is an enlarged perspective view of a conventional printhead employed in transferring dry DNA from DNA transfer films producedusing the assembly of FIG. 1.

[0024]FIG. 3 is an exploded schematic representation of a printer setupshowing the orientation of the print head, the DNA transfer film on theprint tracker, and a multi-slide holder underlying the surface of theDNA transfer film carrying DNA spots for transfer of minute portions ofdry DNA from the spots onto the surface of the glass slides as employedin the process of the present invention.

[0025]FIG. 4 is an enlarged view of a dry DNA transfer spot on the DNAtransfer film showing the sequential shifted pin impact locations for agiven print pin during multiple usage of the DNA transfer film.

[0026]FIG. 5 is a perspective view of the printer incorporating a setupsimilar to that of FIG. 3.

[0027]FIG. 6 is side elevational view of an apparatus for manufacturinga dry DNA transfer sheet in accordance with the principle set forth indrawing FIG. 1 and forming a further embodiment of the invention.

[0028]FIG. 7 is a top plan view of the apparatus of FIG. 6, with thecover pivoted 180° to open position.

[0029]FIG. 8 is a perspective view of a standard 96 well plate with adispensing valve positioned within one of the wells forming a furtherembodiment of the invention.

[0030]FIG. 9 is a vertical sectional view of the dispensing valvecarried by the corner well in the embodiment of FIG. 8.

[0031]FIG. 10 is a side elevational view of an apparatus formanufacturing a dry DNA transfer film forming a further embodiment ofthe invention, with a plurality of side-by-side well plates carrying thedispensing valves of FIG. 9, with projecting tips thereof in contactwith the upper surface of a mylar dry DNA transfer sheet.

[0032]FIG. 11 is a top plan view of the apparatus of FIG. 10, with thehinged well plate holder unlocked.

[0033]FIG. 12 is a perspective view of a standard 96 well plate with acylindrical porous material liquid dispensing wick fitted to the top ofa corner well within the well plate for use with the apparatus of FIGS.10 and 11 and forming a further embodiment of the invention.

[0034]FIG. 13 is a side elevational view of the well plate of FIG. 12.

[0035]FIG. 14 is an enlarged sectional view through lines 14-14 of FIG.12.

DESCRIPTION OF THE PREFERRED EMBODIMENT

[0036] Referring to FIG. 1, that figure illustrates a key aspect of theinvention directed to the creation of a dry DNA transfer film for use ina DNA array test system forming one embodiment of the invention. Afilm/well assembly indicated generally at 10 is formed of an underlying96 well plate 12 of rigid material of rectangular form and having alongitudinal pivot axis X—X. Within a top surface 14 of the well plate12, there are created a series of upwardly open, cup-shaped, cylindricalwells 16 within the well plate top surface 14 of that member in spaced,column and line fashion. The well plate is an industry standard having96 wells in an eight by twelve matrix. In the method or process usingthe assembly 10, initially DNA is separated into individual genes andreplicated many times into a number of such well plates 12. Depending onthe diameter and spacing of the wells 16, one to three 96 well plates 12are sealed at the top 14 of the well plates commonly by an acid etched,frosted plastic film 18 or like transfer media which is both flexibleand resilient, so that it attempts to maintain its flat condition asshown. At least one surface 18 b of the plastic film 18 is etched. TheDNA liquid 50 preferably fills the wells 16, with the DNA in liquid formrepresentative of the individual genes within the many wells of thearray. In the schematic embodiment shown, there is a single well and oneplastic film. Typically, the film 18 is of a size 8½× 11 with rows ofspaced perforations 38 along opposite lateral side edges of the plasticfilm 18. The plastic film may be of a suitable material such as mylar,polyethylene, etc., and the acid etching provides a frosting to at leastthe surface 18 b of the plastic film 18 so that the liquid DNA willphysically attach to the plastic film. The other side 18 a may besimilarly etched to receive DNA dots. After the supply of liquid DNA ofrespective genes to wells 16, which liquid DNA charges may not come tothe top of the wells, the plastic film 18 is sealed to the top or uppersurface 14 of the rigid well plate 12. Sealing may be effected by avacuum seal process well known in the art, or alternative means such asby using a jig or fixture which opens and locks closed and which bothsupports the assembly and permits the inversion of the assembly asindicated by the double headed arrow 48, FIG. 1, for rotation about thelongitudinal horizontal axis of the well plate 12. A foam sheet (notshown) on a cover of the assembly facing the wells may press the mylarfilm 18 against the well plate. After sealing of the plastic film 18 tothe well plate, inversion of the assembly 10 results in gravity depositof the liquid DNA charges 50 in each well location onto the surface 18 bof the plastic film. The frosting of that surface 18 b prevents theliquid DNA from expanding radially from the initial spot and allowsadditional area for physical attachment of the DNA which has aconfiguration and size of the well bore. Initial inversion need last foronly a second or so. This is all the time necessary to effect wetspotting of the surface 18 b with the respective different DNA geneliquid charges 50.

[0037] Almost immediately, the assembly 10 is reinverted back to theposition shown in FIG. 1. The plastic film may be exposed to the air,the liquid spots dried; thereby allowing the film to be slowly andcarefully lifted from the well plate. With the DNA gene spots 50, FIG.4, dried, there is formed a dry DNA transfer film. The DNA transfer filmnamed for its likeness to carbon paper and its use of in a printer fortransferring small segments of the dry DNA spots 50 over the surface 18b of each film 18 is ready for loading onto a printer 60 such as DNAtransfer film 30, FIG. 3. Printer 60 is comprised of a modified pinpoint print head 20 of block form having a face 22 within which ismounted a number of cylindrical, outwardly projectable and retractableprint pins or type fonts. The print pins or font tips in the illustratedembodiment may be 250 microns in diameter and may be cylindrical inform. Tip size varies with array density. Depending on the configurationof the dry DNA dots to be positioned in column and line fashion, anumber of slides as at 44, FIG. 3, may be borne by a slide holder 40.The pin head or font may be rectangular rather than circular in section.Since the printing process is quite similar to a computer controlledprinting apparatus in general, the principal elements of such printingapparatus for printer 60 are shown only in schematic form, FIG. 3. InFIG. 3, the tractor 70 is shown as having sprocket wheels 32 mounted atopposite ends of a shaft, with the sprocket wheels engaging theperforations 38 within the opposite side edges of the DNA transfer film18. In the exploded perspective view, the print head 20 is to the leftof the tractor 70, with the head being of L-shaped configurationincluding a base 26 which pivots about an axis parallel to the axes ofthe sprocket wheel assemblies 32 on transverse shaft or rod 54.Additionally, the head 20 is mounted so as to move at right angles tothe longitudinal axis a of the DNA transfer film 18 on a motor drivenrod 52, thus laterally as per arrow β from side-to-side of the DNAtransfer film 18. Rod 54 may be rotated about its longitudinal axis toallow imprint of a selected pin 24 against the DNA transfer film 18.Such action may be incremental or continuous, as may be the drive θ forthe tractor, FIG. 5. Such drives are indicated schematically, FIG. 3. Amotor as at 36 is connected at 34 to a lower sprocket assembly 32 a toachieve the movement of the DNA transfer film in the direction of itsaxis a. Schematically, a further motor 32 b connected to the bottom ofthe base 26 of the print head 20 via rod 54 may cause the print head toswing clockwise towards and counter-clockwise away from the surface 18 aof the DNA transfer film 18 to position face 22 of the print head inoverlying position to the DNA transfer film. The microscope slide holder40 is positioned beneath film 18 on the tractor 70 and the slides 44maintained in a position to receive by transfer a small segment of a DNAspot 50, FIG. 4, carried on the opposite surface 18 b of the DNAtransfer film which immediately faces but is spaced slightly from themicroscope slide holder 40. A computer or a CPU (Central ProcessingUnit) operating under a program controls movement of the print head 20,the DNA transfer film 18 and the slide holder 40 to determine thelocation of each closely spaced dot 45, FIG. 3, of DNA gene transferfilm spot 50 directly onto the facing surface of a slide 44.

[0038] The slides 44 are precoated with poly-L-lysine, or other knownchemical attractant biomolecule including DNA. Thus, only light impactof the dry DNA spot 50 upon striking of one of the pins 24 of the array,FIG. 2, such as projected pin 24 a, is required to ensure transfer of asufficient amount of the DNA from the film spot 50 to a slide 44 uponimpact of the printer 20 pin head 24. In the typical printer, the printhead therefore travels horizontally, while the tractor riding on aninfinite servo motor moves the DNA transfer film 18 vertically, i.e., atright angles as per β. The DNA gene array transferred from the DNAtransfer film to the slide is only limited by the size of the slideitself. The slide size is only limited by the reader capacity of thesystem. Preferably, the slide holder and the slides 44 thereon are notin contact with the surface 18 b, but under computer or CPU controlraised to lie immediately beneath the surface 18 b of the DNA transferfilm 18, just prior to projection of the print head pin 24 in a limited,light contact with the surface 18 a opposite a dry DNA dot 50 on slidefacing surface 18 b. Such system under computer or CPU control iscapable of pin point transfer of minute surface area dots of DNAdirectly onto the facing side of the glass slides. Minute shifting ofthe print head 20 relative to the DNA transfer film 18 and its tractor70 is effected after each cycle of printing, that is, for a given DNAspot 50, vertically and/or horizontally so that the DNA transfer filmmay be used over and over again. The sequence of alignment and thusprint pin impact position on the opposite face 18 a of the spot 50 inFIG. 4 illustrates shifts laterally; at one, two, diagonally; from twoto three, laterally; three, four, five and six, diagonally; from six toseven, and laterally through eight and nine. Only nine of theincremental shifts of the print head relative to the DNA transfer filmare shown in FIG. 4, since the numerals ten, eleven and twelve have beenused elsewhere in the drawings. Further, the computer or centralprocessing unit may effectively track all of the individual DNA transferfilms for the number of times it has been used, and the use is through acontrolled sequence of shifts such as that illustrated partially in FIG.4. Preferably, the print head is moved to a new starting positionslightly offset from the last for each time the film is reused inaccordance with the schematic illustration at FIG. 4.

[0039] While not in use, the DNA transfer film may be stored underrefrigeration at temperatures ranging from a +4° C. to −80° C.(depending on solvent and concentration). While the illustratedembodiment employs 3×1″ glass slides, such microscopic slides may belarger such as 6×2″, 4×8″, etc. Theoretically, under the systemillustrated and described, there may be in the neighborhood of 400,000DNA gene dots on the glass slide, very closely spaced and generally incolumn and line fashion. Alternatively, the dots may be in staggeredrows, not columns, as such allows greater dot array density. Since theDNA transfer film is flexible and resilient, there is only localizeddeformation of the mylar, polyethylene or other like material film,sufficient to bring the fraction of DNA spot 50 into contact with theglass slide 44 surface depositing the feature 45. Since that slidesurface is coated with poly-L-lysine, there is both a physical andchemical transfer of the DNA from spot 50 on the DNA transfer film 18onto the glass slide. The affinity of the poly-L-lysine for DNA ensuressufficient and consistent concentration of the DNA transferred to createa test dot or “feature” 45 as such dot is known in the industry. Oncethe array of DNA dots is created on the slide or slides of the holder40, the slides are removed, and the completed array is bathed in asolution of two or more fluoresces labeled total genomic tags. Thesetags hybridize (bind) to a particular gene on the array and each timethey bind the fluorescence signal becomes linearly stronger.

[0040] Under a fully automated system, a modified fluorescencemicroscope connected to the computer may automatically read eachlocation on the array and measure the intensity of its signal and theidentity of the signal being produced. By further computer correlationsof data points, one may determine the relationships between any two celltypes and a third variable (drug), or the same cell types between onevariable or more.

[0041] The system of the present invention has significant utility inthe medical field, the health industry in general and the pharmaceuticalindustry, both in terms of manufacture and use or detection andtreatment of medical disease. The print process of the instant systemtakes a significant shorter period of time to create the dry DNA dotarrays on slides such as slides 44, thereby completing such arrays inminutes rather than days that occur with the systems currently creatingarrays utilizing the wet technique where the DNA in wet form isdeposited directly onto the microscope slides. Since the dry DNAtransfer films can be stored indefinitely, the array is quicklyreproducible without lengthy reactions.

[0042] In the past, arrays a.k.a. micro arrays, industry term of storedDNA dots or features required constant cleaning of the array apparatusto deter contamination of the array. In the system of the invention, theprojected pins do not touch the DNA, but are isolated therefrom by themylar transfer film, or like media. In systems where the DNA istransferred in liquid form onto the microscope glass slides, allelements coming into contact with the liquid DNA require periodic andconstant cleaning. Further, by utilizing the frosted mylar or similarplastic film material, there is virtually no spread of the liquid DNA inthe formation of the individual spots 50 on the frosted surface of themylar film, or after removal of the DNA transfer film 18 from the wellplate during the drying of the spots 50. The density using theillustrated embodiment is quite high. With eight rows of twelve samplesof DNA per row using a 24-pin print head 20, one obtains 288 DNA spots50 on a single mylar sheet by using three of the 96 well plates. Withthe use of additional mylar sheets, easily a total of >7200 DNA dotcombinations may be effected on two side-by-side glass slides 44 withina common slide holder like that at 40, using the setup of FIGS. 3 and 5.Further, in the creation of the DNA transfer film 18, automatic recordkeeping is facilitated since one may readily type data onto the reverseside of the mylar film, i.e. the date of the test, time, identificationof the subject, type of test, etc. Not only does one have a thoroughrecord of the test work done, but the actual proofs as a result oftesting are attached as dry DNA content to the opposite side of themylar film. All of this is done without the mess of dealing with liquidDNA, except in the first instant in a highly effective and quick mannerproducing the initial DNA spot form transfer sheets and then employing aconventional automated printing apparatus such as that at FIGS. 3, 5, toeffectively transfer the dry DNA content to the glass slide in a form topermit ready optical testing for mutant content, etc. The flow diagramdescribed in this specification is set forth in chart form as Chart Ahereafter. CHART A COMPUTER PROGRAM (1) Input plate # Input contents ofeach well 1-96 ↓ (2) Input # of slides to be used Input size of slide tobe used Input array density (or automatic) Input Film # Input # of filmto be used Input Density of film array ↓ ↓ (3) Output:location of thearray on slide as map for user and reader computer if not the arrayercomp. ↓ (4) Output:force applied by print head for each location, forconsistency of DNA concentration transferred ↓ (5) Arrayer/Reader outputa) Array contents  i. fluorescence @ each print dot location(color/intensity)  ii. expression level of gene @ each location  iii.correlation between dots (locations)  iv. correlation to previous dataon same subjects or same drug, etc.

[0043] Turning to FIGS. 6 and 7, there is shown an apparatus 100 formaking dry DNA transfer sheets in accordance with the present invention,and in the manner generally depicted in FIG. 1. The apparatus 100consists essentially of a table 110 having a horizontal base 112, fromwhich extends upwardly and longitudinally centered between the ends of apair of laterally spaced legs 114 pivotably mounting a table top 120 viaa horizontal table top hinge pin 128 extending through table topvertical extension or raised end 124 and each leg 114. A fixed,vertically upright stop 116 underlies the table top 120 near the end ofthe table top 120 remote from the hinged pivot connection to legs 114.The fixed stop 116 is of a vertical height such that it abuts the bottomsurface 120 b of the table top to support the table top in a horizontalposition. To the opposite side of the table 110 is pivotably mounted apivotable stop 118 which is pivoted at its lower end via pivot pin 119.The pivotable stop 118 is centered laterally on the base 112. Thepivotable stop 118 rises to a vertical height above that of fixed stop116. A hinged cover 122 overlies the table top 120 and is hinged to thetable top raised edge 124 by screws or like fasteners (not shown) and toa side edge of cover 122. The hinge 130 permits the cover 122 to berotated from a position overlying the table top 120 through 180° to anoppositely directed horizontal position as shown in dotted lines in FIG.6, and in solid lines in FIG. 7. As such, the apparatus cover rotateslike a book into a full open position, FIG. 7. Because of the locationof the hinge 130, the top surface 122A comes into contact with the topsurface of the movable stop 118 when the movable stop is rotated fromits inclined dotted line position shown in FIG. 6 at 118′ to its fullline position. A lower face 122B of cover 122 carries a rectangularrecess which receives a foam sponge rectangular sheet 123 sized on theorder of a dry DNA transfer sheet formed of mylar or other material asdescribed in this specification. Projecting downwardly from the bottomsurface 122B of the cover 122 are a number of dry DNA transfer sheetlocation pins 134, at least one at each of the four corners of mylar dryDNA transfer sheet 18 for overlying the three side-by-side well plates12. Plates 12 as seen in FIG. 7 are received within spaced parallelgrooves 140 opening outwardly at one end of table 120 and within thetable top 120A and sized slightly larger than the width of the elongatedwell plates 12. The well plates are positioned within the grooves 140 soas to be appropriately positioned to align with the common mylar dry DNAtransfer sheet 18. A pair of laterally spaced projections 122C arecarried by cover 122 near the lateral center line of the table cover 122defining a slot which receives a pivotable thumb screw assembly 142including a shank pivotably mounted at its lower end to an outboard edgeof the table top 120 via pivot pin 144. The assembly 142 includes a wingnut 143 which when unscrewed from the position shown in FIG. 6 allowsthe shank to pivot outwardly as shown in FIG. 7 to release the cover andpermit its shifting from the full line position of FIG. 6 to the dottedline position in that figure and the full line position in FIG. 7. Thetwo basic components, therefore, consisting of table 120 and cover 122open like a book from the condition shown in FIG. 6 to that of FIG. 7.The apparatus 100 further comprises as seen in FIG. 7 a vacuum groove136 within the bottom surface 122B of cover 122 connected to a source ofvacuum indicated by an arrow V, FIG. 7, via vacuum line 138. With theapparatus open like a book, FIG. 7, mylar dry DNA transfer sheets 18 maybe sequentially mounted via the perforations therein onto location pinsalong opposite sides of the vacuum groove and exterior of the same sothat the bottom surface of the mylar sheet or film 118 is in contactwith the bottom face 122B of cover 122. Application of vacuum pressureby vacuum source V causes the mylar sheet 18 to be maintained in exactdesired position, whereupon with one, several or all of the wells of thewell plates 12 being loaded with liquid DNA (or other, similarsolutions), the cover 122 is pivoted counterclockwise from the dottedline position shown in FIG. 6 to the full line position. At this point,the pivotable thumb screw assembly 142 is rotated from the positionshown in FIG. 7 to a vertical upright position, and the wing nut 143rotated on threaded shank so as to clamp the cover 122 and thus themylar sheet 18 against the upper surface of the upright open well plate12, compressing the sponge sheet 123 to effect a seal between theinverted top surface of the mylar film 18 and well plate 12. A fixedassembly is achieved, i.e. table top 120 and cover 122, corresponding inprinciple to that of film/well plate assembly 10, illustratedschematically in FIG. 1. The assembly is rotated clockwise via hingepins 128 after pivoting pivotable stop 118 from its full line verticalposition to a dotted line inclined position 118′, FIG. 6, the result ofwhich is to cause the liquid DNA within given wells 16 of the three wellplates 12 to make physical contact with the facing surface of the mylarsheet 18 and forming distinct, relatively large diameter, spaced dots.Thereafter, the rigid assembly of the cover 122 and the table top 120 ispivoted counterclockwise about the axis of hinge pins 128 back to theposition shown in FIG. 6, whereupon the pivotable thumb screw assembly140 is released by rotating the wing nut 143 oppositely on the threadedstem of that apparatus to loosen the lock which, after pivoting from avertical to a horizontal position, permits the now released cover to berotated clockwise again to the extent of the dotted line position ofFIG. 6 and full line position of FIG. 7. The wet DNA spotted transfersheet 18 may either be dried in place, or removed for drying with theapparatus ready to repeat the process to create a series of multiplemylar dry DNA transfer sheets.

[0044] Referring further to FIGS. 8, 9, 10 and 11, an additionalembodiment of the invention utilizes an apparatus indicated generally at200, FIGS. 10 and 11. Apparatus 200 has some common components to theapparatus at 100 of the prior described embodiment and functions toproduce a series of DNA transfer sheets by using a different technique.

[0045]FIG. 8 illustrates perspectively one of three identical wellplates with individual upwardly open wells 16, one of which at the leftbottom corner has positioned within the interior of this U-shapedupwardly opening cavity a self-actuated dispensing valve indicatedgenerally at 250 and forming the principal component of this furtherembodiment of the invention. The dispensing valve 250 in accordance withFIG. 9 is comprised of a cylindrical valve body 252 having an axial bore254 of relatively small diameter and a large diameter counterbore 256which opens outwardly at the opposite end of the cylindrical body 252.The valve body 252 has opposed faces 260 and 262 and an outercylindrical wall 258. It houses internally a movable valve member orplunger indicated generally at 264 consisting essentially of a smalldiameter stem 264A enlarged intermediate of its ends by a conical shapedvalve stopper 264B. The stopper 264B is radially larger than thediameter of bore 254. The body 250 includes a shallow axial recess 278within end face 260. A radial circumferential recess 276 extends over aportion of the axial length of body 252 from face 262, within the outerperipheral wall 258 of that member. Additionally, a circular groove 272of short depth and short axial height is formed within the largerdiameter portion of body 252, within which may be fitted an O-ring 274,sealing body 252 with the inner peripheral wall of the well 16 withinwhich it is received, FIG. 8. Near the open end of counterbore 256, aninterior groove 253 receives a triangular plan shaped stem guide andfill plate provided with a small diameter axial bore 255 through whichstem 264A projects. A compression coil spring 270 is interposed betweenguide plate 255 and the conical valve stopper 264B biasing the stopper264B to valve closed position, with the tapered portion of the valvestopper in contact with a valve seat 282 defined by bore 254.

[0046] Once the valves 250 are in place in the respective wells 16 ofwell plate 12, FIG. 8, the well plate acts as a dispensing mechanism forthe liquid DNA. As seen in FIG. 8, the projecting tip 284 of the movablevalve member or plunger 264 extends outwardly beyond a ring stopper 286defined by axial recess 260 which acts as a downward stop against anupper surface of a mylar dry DNA transfer sheet or similar media, whenone or more well plates 12 utilizing the dispensing valves 250 areemployed with the apparatus of FIGS. 10 and 11.

[0047] With the liquid charges within the wells 16 of well plate 12, thedispensing valves 250 are upturned from the position shown in FIG. 9 andinserted into the upwardly open wells to the extent of the axial lengthof the outer peripheral recess 276 within valve body 250 and defining acircular shoulder 277. Preferably, annular groove 272 on the outerperiphery of the cylindrical valve body 252 carrying O-ring seal 274prevents leakage of the liquid DNA from the individual cells between thevalve body 252 and the sidewalls of the cells 16 carrying the dispensingvalves 250.

[0048] The apparatus 200 depicted in FIGS. 10 and 11 permitspredetermined volumes of DNA liquid to be dispensed through thedispensing valves onto the upper surface of a mylar dry DNA transfersheet 18 as in the previous illustrated embodiment. The apparatus 200includes a table indicated generally at 210. Table 210 includes a tabletop 214 supported by short height legs or feet 212 at the four cornersin similar fashion to the embodiment of FIGS. 6 and 7. A vacuum line 242connects to a vacuum groove 240 within the top surface 214A of the tabletop and may be coupled to a source of vacuum at 243 for holding down andin place on the table top a mylar dry DNA transfer sheet located by wayof location pins 220 prior to vacuum application. Laterally spacedrisers 216 provide a hinge connection to one end of a pivotable wellplate holder 224, via an elongated hinge pin 226 passing throughrespective risers 216 adjacent their upper ends and the end of wellplate holder 224. As such, well plate holder 224 is mounted for rotationthrough an arc of approximately 180° from the position shown in FIGS. 10and 11 so that the upper surface 224A comes into contact with the upperend of a fixed stop 222 mounted to the upper face 214A of the table top,at some distance to the right of risers 216. This permits freedom toproperly position the mylar dry transfer sheet 18 in the position inFIGS. 11, 12 for receiving spaced drops or volumes of liquid DNA of theDNA solution to form the appropriate spot on the surface of the film 18.After mounting of the film 18 to the table top, the hinge well plateholder is rotated counterclockwise to the position shown in the drawingFIGS. 10, 11. The end of the hinge well plate holder 224 opposite thatof the hinge connection via hinge pin 226 is provided with a U-shapedslot 225 for receiving a reduced diameter threaded portion 232 of apivoted locking pin 231 forming an element of thumb screw assembly 230.The locking pin 231 is pivotably mounted via a transverse pivot pin 237to the table top 214 via a pair of laterally spaced ears 236. A thumbscrew locking knob 234 having a tapped axial bore is threaded to thereduced diameter threaded portion of locking pin 231. The bottom surface224B of the well plate holder 224 rests on a shoulder or stop 233 at apoint along the locking pin 231 to maintain the hinged well plate holderspaced some distance above the upper surface 214A of the table top 214and in a horizontal position. Three laterally spaced rectangular holesor openings 238 are formed within the hinged well plate holder 224, theopenings 238 being sized to reduced width base portions 12′A of the wellplates 12′ as seen in FIG. 8. Grooves 239 are formed within the toplongitudinal side edges of the well plate 12′, thereby defininglaterally opposite flanges 239 along the sides of the well plate. Thus,a portion of the well plate 12′ adjacent to the upper surface of thatelement is narrower than the portion proximate to the bottom of the wellplate. The flanges 239 function as stops to limit the extent of verticalmovement of the well plates 12′ when the reduced width portions areinserted within respective holes or openings 238 within the well plateholder 224. Initially, the well plates 12′ are gently lowered into theopenings or holes 238 to the extent where the tips 284 of plungers 264contact the upper surface of the mylar sheet 18 as per FIG. 10. In thisembodiment, there is no need to flip flop the well plates 12′ to depositliquid DNA on the mylar film by gravity deposition. When the tips 284 ofthe stoppers 264 touch the mylar film, all that is required is a slightdownward pressure applied to the well plates, which may be manually orautomatically effected to cause the radially enlarged tapered wellstoppers to move away from their valve seats 282, thereby permitting theDNA solution L to escape from counterbore 256 of each valve body 252 foreach valve 250. Simultaneously, circular ring stop 286 of the valve bodyabuts the upper surface of the mylar film 18, with the liquid DNA inthis embodiment filling a cavity defined by the vertical height B ofrecess 260 and the interior diameter A of the ring stop 286. Exact,minute precise dimensions are required for the valve member to effect asmall liquid charge deposit by each of the dispensing valves 250 capableof spot wetting of the transfer media. Alternatively, the volumetriccontrol of the liquid DNA charge at each spot location on the mylartransfer film 18 may be determined by the extent of time that thedispensing valve 250 is open and determined by the dimensions of theflow paths defined by the stopper 264 and the axial bore 254 within thevalve body 252.

[0049] Once the spot wetting of the mylar sheet is accomplished, thepressure applied to the well plates is terminated and the valvesreclose. The valves 250 automatically close due to the force of thecompression coil spring interposed on the stem 264A with the plunger 264closing on valve seat 282 for each valve. Thus, even when the well plate12′ is inverted from the position shown in FIG. 8, no leakage willoccur. Thus, dispensing of a liquid volume is carefully controlled withresealing of the liquid DNA within counterbore 256 of the valve memberat the termination of the spot wetting of the mylar 18.

[0050] Further, upon release of pressure on the three well plates 12A,the thumb screw 234 may be backed off and loosened to the extentpermitting pin 31 to be rotated from a vertical upright position, FIG.10, to a horizontal position, freeing the hinged well plate holder 224.This permits its rotation clockwise to the extent of permitted by fixedstop 222 and allowing access to the exposed mylar sheet 18 for dryingprior to removal or for removing and subsequent drying of the liquid DNAspots after their creation. With the hinged well plate holder pivotedclockwise out of the way of the mylar sheet area, a new mylar sheet 18may be positioned via the pins 220 and vacuum pressure reapplied to thesucceeding sheet.

[0051]FIGS. 12, 13 and 14 illustrate a further embodiment of theinvention, in which a well plate 12′ identical to that at 12′, FIG. 8,is employed in the apparatus of FIGS. 11 and 12 as depicted or withslight modifications thereto. In this embodiment, the top face 12′Bcomes into close proximity to an underlying mylar dry DNA transfer sheet18 to allow a thin layer of liquid DNA film on a special driplessapplicator wick 290, FIG. 14, to make contact with the upper surface ofthe mylar film 18 and to create a circular spot corresponding to thediameter of the applicator wick. The inverted T-shaped well plate 12′ ofFIG. 12 is provided with a plurality of cup-shaped wells 16 in a columnand line fashion. A singular well is shown in FIG. 12 as receiving anapplicator wick 290, the cross-section of which is shown in FIG. 14. Theapplicator wick 290 is of cylindrical form, having an outside diameterslightly larger than the inside diameter of a well 16 and having alength so as to project into the liquid DNA charge L. A radiallyprojecting circular rib 294 is integral with the cylindrical body 292forming a stop to define a precise axially projected position for thewick upper surface 290A so as to create through capillary wicking actionpassage of the liquid DNA or DNA solution onto the outer axial surface290A of the applicator wick. This achieves permitting a DNA solutionblotting action upon inversion of the well plate 12′ and placement intoposition above the mylar sheet 18, FIG. 10, in place of the well plate12′ carrying the dispensing valves 250 of the prior described embodimentof FIGS. 8-11. The dimensions of the well plate and the dimensions ofthe applicator wick for each well 16 are such that a slight depressionof the inverted one or more well plates 12′ causes momentary contact ofat least the liquid DNA film 290 on the axial outer surface 290A of theapplicator wick with the facing surface of the mylar film 18 at eachwell position 16 on the well plate carrying an applicator wick 290 andbeing loaded with liquid DNA in accordance with the showing in FIG. 14.The volume of the well is defined by the bottom surface of the disc290B.

[0052] The sequence of events using the embodiment of the invention ofFIGS. 12-14 is the same as that for the prior embodiment, utilizing thedispensing valve 250 within each selected well 16, by employing theapparatus of FIG. 10. The well plate holder is initially pivotedclockwise from the position shown in FIG. 10 so that its end remote fromthe pivot axis of pin 226 lies in contact with the upper surface of stop222. A mylar sheet such as that at 18 is positioned on the upper surface214A of the table top and positioned by way of position pins 220 in themanner of the prior embodiment. The well plate holder 224 is thenrotated counterclockwise (217 depiction of angular rotation) 180° tooverlie the mylar sheet 18. The well plate holder may be locked inposition using mechanism 230 as in the prior embodiment, and preferablythree identical well plates with DNA liquid within the wells 16 andclosed off by the applicator wicks 292, penetrating the well to a fixedpoint controlled by flange 294, are inverted from the condition shown inFIGS. 12, 13 and 14 and placed in respective holes or openings 238, withthe flanges 239 limiting that insertion action, but placing the axiallyouter surfaces 290A of the applicator wick immediately above or incontact with the facing surface of the mylar film 18, whereupon theliquid DNA due to the porosity of the foam material or other wickmaterial making up the applicator wick 292 causes a thin layer of liquidDNA to form as a film as at 290 which is blotted off as a result ofmomentary contact between the applicator wick 290A and the facingsurface of the mylar film 18 with like spaced liquid DNA spots beingformed over the face of the mylar film in mirror image fashion to thewells 16 which are actively supplied with liquid DNA prior to insertionof the applicator wicks 292. The applicator wicks therefore perform twofunctions, one sealing the liquid DNA within the well 16 in the volumenot occupied by the wick body 292 and facilitating by capillary action aconstant replenishment of the liquid DNA film 290 on the axially outersurface 290A of the applicator wick. Upon completion of wet spotting,the locking mechanism is loosened and rotated out of the way of thepivotable well plate holder 224. Thereafter, the holder with the wellplates 12′ can be rotated through a 180° arc clockwise until the top ofthe well plate holder contacts the upper end of fixed stop 222 uponwhich it rests, allowing the operator to remove the now wet DNA spottedmylar film 18 and replace it with a new succeeding sheet. The removedsheet upon drying forms a dry DNA transfer sheet which may be used inthe printing apparatus as described with the prior embodiment, or storedunder appropriate temperature prior to such printing use.

[0053] It should be apparent that changes and modification may be madewithout departing from the spirit of the invention as claimed. Forinstance, the printing apparatus as shown in FIGS. 2-5 evidences onlyone type of commercially available printing apparatus capable ofutilizing the dry DNA transfer media in sheet form, endless loop form,tape form, rigid substrate form or otherwise, and which a printingapparatus may achieve imprinting of DNA particles sized to the printfont or print pin dimensions by impacting the back face of the printmedia carrying the dry DNA spots to create a DNA dot of micron size ontothe facing surface of an underlying substrate. Impact printing involvesforce plus movement. Alternatively, pressure plus movement such as byrubbing may be employed to transfer dry DNA spot material from atransfer media onto the facing surface of a rigid glass substrate suchas a glass slide or the like.

[0054] It should also be apparent that while the invention has beendescribed in detail with several embodiments utilizing a mylar sheet orfilm whose surfaces are roughened to receive the liquid DNA charge usingthe apparatus within the drawing figures, such print media may beconstituted by a flexible tape carried by and movable between a feed andtake-up spool. A transfer media may take the form of a porous sheet ofpaper which incorporates means for preventing radial dispersion ofliquid DNA in forming the dry transfer media radially from one liquidDNA spot to another. Such porous paper type print media may beconstituted by a laminate structure having circular areas sized andlocated corresponding to the respective wells providing the liquid DNAto achieve multiple spots in staggered or columnar and line fashionusing the apparatus of the present invention. Alternatively, a porouspaper sheet may be embossed with circular rings sized to the diameter ofthe wells of the well plate and in like numbers, with the embossmentspreventing the radial dispersion of the liquid DNA through the porouspaper beyond the dimension of the indentation corresponding to the welldiameter of the wells within the well plate. Such porous print media isseen as similar, but not identical to carbon paper, with the carbonsurface content being physically equivalent to the dry DNA spots on thedry DNA transfer sheet. The porous paper form of dry DNA transfer mediacan be formed of a porous material which impedes radial dispersion ofthe liquid DNA spots during and subsequent to spot formation and priorto drying of the same. Drying may be accomplished by exposure to air,hot air drying, or infrared radiation to speed up the process of thecreation of the dry DNA transfer media.

[0055] It should be kept in mind that while the specification and claimsrecite a DNA wet solution and dry DNA spots and dots, respectively, theclaims and the invention are not limited thereto, but broadly cover theutilization of and transfer of a concentrated solution of DNA, RNA,protein and biomolecule from one or more well plates or other containerto an appropriate transfer media utilizing as an imprinting substrateany type of porous paper, film, flexible resilient sheet, or rigidsubstrate that inherently or by way of treatment or modification willbleed liquid, i.e. the concentrated solution in a Z direction, whileinhibiting or limiting bleed laterally or radially, with that substratepreferably being an acid etched polymer film such as mylar. Further,while the printing mechanism, which is schematically illustrated in thedrawings and described in some detail in the specification, uses a motordriven tractor to drive a transfer media in sheet or endless loop formvia sprockets having radially projecting pins whose ends insert intoholes along the sides of the transfer sheet or endless loop, movement ofthe dry DNA transfer media may be effected by a position control throughthe use of laser beam or light locating means to facilitate by lateralmovement of a print head bearing multiple projectable pins or type fontsuch that a given quantity of the DNA, RNA, protein or other biomoleculedry spot on the transfer media is mechanically transferred by impactforce or rubbing pressure onto a facing glass substrate which in turnmay be shifted towards and away from the dry DNA transfer media.

[0056] Further, while vacuum grooves and vacuum application isillustrated as a means for maintaining the position of the ink printingsubstrate, other means such as mechanical clamping may be employed toensure sealing of that member to the face of the well plate or an arrayof well plates prior to the transfer step. While preferred exemplaryembodiments of the invention have been described in detail, it should beunderstood that other variants and embodiments thereof are possiblewithin the spirit and scope of the claims, with the latter being definedby the appended claims. Further, all features described in thespecification, recited in the ensuing claims and shown in the drawings,may be essential to the invention, either individually or in anyarbitrary combination with one another.

[0057] It should be understood that various changes can be made withoutdeparting from the spirit and scope of the invention. The preferredembodiment of the invention is illustrative only and modifications andvariations in content of the embodiment and in the process steps in theproduction of the components of the dry DNA array system would occur tothose of skill in this art without deviating from the invention. Withinthe scope of the appended claims, the invention may be practiced otherthan as specifically described or shown above.

What is claimed:
 1. Process of forming a dry DNA transfer mediacomprising: placing liquid DNA solutions within respective upwardly openspaced cup-shaped wells within a well plate; causing localized momentarycontact between an ink printing substrate and the DNA solutions withinrespective wells to create wet DNA solution spots at correspondinglocations on said ink printing substrate; and drying said spots to formsaid dry DNA transfer media for use in forcible impact or rubbingprinting of dry DNA dots onto a facing glass test substrate from saidselected dry DNA spots on said media.
 2. The process as claimed in claim1 , wherein said process further includes sealing said ink printingsubstrate face-to-face against said well plate in a position coveringthe openings of said well to create a sealed assembly and inverting saidsealed assembly to wet coat the face of said media to create DNAsolution spots at positions corresponding to the positions of saidwells.
 3. The process as claimed in claim 1 , wherein said ink printingsubstrate comprises one material of the group consisting of plastic,glass, nitrocellulose, acetate and paper.
 4. The process as claimed inclaim 3 , wherein said ink printing substrate comprises a mylar sheet,and wherein said mylar sheet has a roughened surface facing said wellopenings.
 5. The process as claimed in claim 1 , further comprisingporous wicks fitted within each cell having one end contactable with theDNA solution within the wells and having another end of the wick atleast flush with the surface of the well plate bearing the wells suchthat a layer of DNA solution forms on the end of the wick exposed at thesurface of the well plate, and said process further comprises placingsaid ink printing substrate in contact with the coated ends of saidwicks to form wet DNA liquid spots on said ink printing substrate. 6.The process as claimed in claim 5 , further comprising the step ofinverting an assembly of said well plate and said ink printing substrateto ensure DNA solution spotting of the ink printing substrate at saidwell locations.
 7. A process forming a plurality of spaced dry DNA dotson a glass substrate for testing purposes, said process comprising:placing liquid DNA solution within an array of spaced cup-shaped wellswithin a well plate; causing localized, momentary contact between an inkprinting substrate and the liquid DNA within respective wells to createa corresponding series of spaced wet DNA spots on said ink printingsubstrate; drying said spots to form a dry DNA transfer media andplacing said dry DNA transfer media in proximity to said glasssubstrate, with said dry DNA spots facing a surface of said glasssubstrate; and selectively, locally pressuring impacting the oppositeface of said dry DNA transfer media behind said dry DNA spots to causemechanical transfer of dry DNA dots from said media spots to the facingsurface of said glass plate.
 8. A high throughput process for forming adry DNA transfer film comprising: placing separated, replicated DNAgenes solubilized in a solution within respective wells of a generallyrigid well plate having within an upper surface thereof, a plurality ofclosely spaced wells; fixedly mounting a thin flexible resilient filmagainst said upper surface and sealed to the upper surface of the wellplate and effecting a rigid film plate assembly; inverting said rigidassembly to cause the DNA solution to physically, locally wet coat theroughened surface of the film while preventing the DNA gene solutionfrom running radially from one spot to another; reinverting saidassembly to its initial position; removing the DNA gene solution spottedfilm slowly from the well plate; drying the DNA gene solution spotcoating thereon and thereby forming a dry DNA transfer film capable ofphysical and chemical dry transfer of DNA to a test substrate.
 9. Theprocess as claimed in claim 8 , wherein said step of drying the DNA genesolution spot coating comprises air drying.
 10. The process as claimedin claim 8 , wherein said step sealing said thin flexible resilient filmto said well plate top surface comprises forming a vacuum seal betweensaid well plate and said thin flexible resilient film.
 11. A dry DNAtransfer film formed by the process comprising: placing separated,replicated DNA genes solubilized in a solution within a plurality ofspaced cup-shaped wells within a generally rigid well plate, with saidcells opening to a top surface of said well plate; fixing a flexibleresilient film having a roughened surface to said top surface of thewell plate, with said roughened surface facing said well plate topsurface; effecting a rigid film plate assembly; inverting said assemblyto cause the DNA solution to physically, locally wet coat the roughenedsurface of the film, with the roughened surface causing the DNA genesolution to cling to the film as spaced dots corresponding to the wellposition while preventing the DNA gene solution from running radiallyfrom one spot to another; reinverting the assembly to its initialposition; removing the DNA gene solution spotted film from the wellplate; and drying the DNA gene solution spots to form a dry DNA transferfilm capable of physical and chemical dry transfer of the DNA to a testsubstrate.
 12. A dry form DNA analyzing process comprising the followingsteps: prefilling respective separated, replicated DNA genes solubilizedin a solution within a plurality of upwardly open spaced wells within anupper surface of said rigid well plate; sealing a flexible resilientfilm at a predetermined position on the upper surface of said rigid wellplate, with said film covering the prefilled wells; forming a fixed,sealed assembly between the well plate and the overlying thin flexiblefilm; inverting the assembly to transfer DNA gene solution as spacedspots to the facing surface of the film over localized areas of saidfilm defined by respective wells; reinverting the assembly; removing thefilm and drying the transferred DNA gene solution spots to thereby forma dry DNA gene transfer film; placing the dry DNA gene transfer film ina position facing a flat glass test substrate and momentary pressing theface of the dry DNA gene transfer film opposite that bearing said spotsat spot locations, causing pieces of dry DNA to locally contact the testsubstrate such that portions of the dry DNA spots and mechanicallytransferring from the transfer film to the test substrate by physicalaction and chemical attraction; sequentially repeating the last step atdifferent localized dried DNA spot locations on the dry DNA genetransfer film to complete a dry DNA gene test dot array on the testsubstrate; and bathing the dots with two or more total genomic tagfluoresces to hybridize the tag to a particular gene of the array andoptically scanning the array to identify dots containing fluorescentlylabeled DNA to determine the existence of mutants or lack of the same.13. The process as claimed in 12, wherein the step of causing dry DNA tolocally contact the test substrate comprises feeding the film in a firstdirection while moving a multi-pin print head across the film at rightangles to the direction of feed of the film and impacting a selectedprint head pin against the film at the back of a preselected DNA spotlocation to forcibly imprint a portion of the DNA spot onto the facingsurface of the glass test substrate.
 14. The process as claimed in claim13 , wherein said dry DNA gene transfer film is supported on a printtractor for movement in a direction of the film longitudinal axis viaperforations extending along laterally offset edges of the film engagingmotor driven sprocket wheels, wherein the film underlies the print headand overlies said glass test substrate, and wherein the print head movestransversely across the top of the DNA transfer film.
 15. The process asclaimed in claim 14 , further comprising moving said glass testsubstrate incrementally towards and away from the plane of said film,cyclically timed to the projection of print head pins within said printhead, such that said glass test substrate is placed immediately adjacentto the surface of the dry DNA transfer film at the moment of print headpin impact, with the surface of the DNA transfer film opposite to thatof selected projected print head pins.
 16. Apparatus for forming a dryDNA transfer media comprising: a table, said table including anelongated table base extending horizontally, a vertical riser extendingupwardly from the base intermediate of ends of the base, a horizontalflat table top hinged at one end to said vertical riser, a fixed stopmounted upright to said base and underlying said table top remote fromsaid first hinge, a cover overlying said table and hinged by a secondhinge to said table top so as to extend parallel to said table topoverlying the same in first position and being rotatable 180° to an openposition extending parallel to the table top and to the side of saidcenter leg opposite that of said table top, a pivotable stop mounted tosaid base to the side of said center post opposite that of said fixedstop and underlying said cover when said cover is pivoted from saidfirst position to said second position and being of a vertical height soas to maintain said cover horizontal when in said second position, thebottom surface of said cover being flat and including location pins forlocating and fixing the position of said media on said bottom surface ofsaid cover, means for positioning at least one well plate in fixedlateral and longitudinal positions on the upper surface of said tabletop at a position aligned with that of said transfer media, clampingmeans for fixing said cover in spaced overlying position on said tabletop, with said transfer media overlying said well plate, said well plateincluding a plurality of spaced upwardly open wells adapted to carryseparated, replicated DNA genes solubilized in a solution withinrespective wells, said apparatus further comprising means for sealingthe transfer media against the upper surface of said well plate andcovering said upwardly open wells, whereby with said cover in saidsecond position said transfer media may be fixed in a designatedposition on the bottom surface of said cover via location means, andsaid at least one well plate may be fixedly positioned at apredetermined position on the upper surface of said hinged table top,wherein by rotation of said cover 180° from said second position to saidfirst position and by operation of said clamping means for fixing saidcover in spaced overlying positions with respect to said table top, afixed assembly may be achieved, whereupon subsequent rotation of saidfixed assembly including said table top through a 180° from its positionagainst the fixed stop in a direction towards said movable stop and bymoving said movable stop to an inclined position on said table base,said assembly is inverted to cause the DNA solution to physically,locally wet coat the surface of said media creating spaced spots of DNAsolution, whereupon the assembly may be pivoted about said first endthrough 180° to the extent of said table top contacting the fixed stop,whereupon the clamping means may be released permitting the cover torotate from its first position to its second position to allow the mediawith the wet DNA coated spots to be removed from the table top and saidspots to dry to thereby form said dry DNA transfer media.
 17. Theapparatus as claimed in claim 16 , further comprising a resilient foamsheet interposed between the bottom surface of the hinged cover and saidtransfer media and being of a thickness such that with the clampingmeans fixing the cover in spaced overlying position with said table top,said resilient foam sheet compresses the transfer media against theupper surface of the at least one well plate to seal said transfer mediaagainst the well plate surface.
 18. The apparatus as claimed in claim 16, wherein said at least one well plate comprises a plurality of wellplates, and wherein said table top includes a like number of grooveswithin which respective well plates are positioned for positivelylocating said well plates on the upper surface of said table top. 19.The apparatus as claimed in claim 16 , wherein a vacuum groove isprovided within the bottom surface of said hinged cover underlying saidtransfer media, and wherein said vacuum groove is connected to a sourceof vacuum via a vacuum line to fix the transfer media in position asdetermined by said location means.
 20. The apparatus as claimed in claim16 , wherein said location means comprises location pins projectingoutwardly of the bottom surface of said hinged cover, and said transfermedia includes holes sized to said pins and positioned to receive thepins.
 21. Apparatus for forming a dry DNA transfer media capable ofphysical and chemical dry transfer of DNA to a test substrate, saidapparatus comprising: a table, said table including a flat horizontalbase, location means for locating a transfer media at a fixed positionon an upper surface of said table top, riser means adjacent one end ofsaid transfer media, a flat rectangular well plate holder pivoted at oneend to an upper end of said riser means for pivoting of said well plateholder through an arc of at least 90° between a position overlying saidtransfer media and extending parallel thereto and a raised position, alocking pin and support means at an end of said well plate holder remotefrom said hinge and including a stop for supporting said well plateholder in a fixed position overlying said transfer media and parallelthereto, at least one elongated well plate hole within said well plateholder for receiving a well plate, said well plate including a pluralityof spaced upwardly open cup-shaped wells for receiving separated,replicated DNA genes solubilized in a solution within respective wells,and means carried within said well for sealing off the upper open endsof said wells and for facilitating locally wet coating the facingsurface of said transfer media when said at least one well plate isinverted and inserted within a correspondingly sized opening within saidwell plate holder to the extent of said means closing off the open endsof said wells contacting the surface of said transfer media, whereuponrelease of said clamping means and rotating of said pivotable well plateholder to said raised position moves the well plates away from the wetDNA coated surface of said transfer media to permit removal of saidtransfer media from the upper surface of said table and to allowreplacement thereof by a new uncoated transfer media and the processrepeated.
 22. The apparatus as claimed in claim 21 , wherein said meansmounted within said wells comprise: dispensing valves, said dispensingvalves each comprising a cylindrical upwardly open valve body having anaxial bore and a counterbore, said axial bore extending through a bottomface of said valve body, said counterbore opening outwardly of a topface of said body, a movable valve plunger mounted coaxially within saidbore and counterbore, a triangularly shaped stem guide and fill openingplate mounted within said counterbore adjacent said top face andincluding an axial bore receiving one end of said stem, said stemforming a part of said plunger and including a radially enlarged taperedvalve stopper seated on an end of said axial bore for closing off saidaxial bore, biasing means biasing said plunger in valve closed position,said plunger terminating in a reduced diameter tip projecting axiallybelow said bottom face, and wherein said dispenser valves are invertedand sealably positioned within the open end of said wells within saidwell plate, such that when the well plate is inverted after positioningof the dispenser valves within respective wells and with DNA solutionwithin the wells, the tapered valve stoppers prevent release of DNAsolution until the projecting tips of said movable valve plunger contactthe facing surface of said transfer media to open said valve plungeragainst said biasing means to effect local wetting of the transfer mediaat positions corresponding to the positions of the spaced wells withinthe well plate.
 23. The apparatus as claimed in claim 21 , wherein themeans closing off the openings within the space wells of the well platecomprise applicator wicks, the wicks being sized slightly larger thanthe internal diameter of the wells and being fitted thereto and havingone end projecting outwardly from the upper surface of the well plateand having another opposite end projecting downwardly within the wellfor contact with the DNA solution therein, and said one end being wettedby capillary action upon wick contact with the DNA solution such that aliquid DNA film forms on said one end of the applicator wick projectingoutwardly from the upper surface of the well plate such that uponinversion of the well plate the DNA solution film on the projecting endof the applicator wick is contactable with the facing surface of thetransfer media to create said wet spots of DNA solution duringdepression of the well plate within the well plate opening of the wellplate holder.
 24. The apparatus as claimed in claim 21 , wherein avacuum groove is formed within the upper face of the table top beneaththe transfer media, and a vacuum line couples the vacuum groove to asource of vacuum so as to vacuum fix the transfer media in a positiondetermined by the location means.
 25. A dry DNA transfer mediacomprising one member of the group consisting of a flexible film, paper,nitrocellulose, plastic, glass for overlying a top surface of agenerally rigid well plate carrying separated, replicated DNA genessolubilized in a solution within respective spaced upwardly open cellswithin said well plate, said media including DNA solution barriers atspaced locations within said media at locations corresponding to saidwells to permit DNA solution local wet coating upon sealing of thetransfer media to the surface of the well plate bearing said upwardlyopen well, but preventing the DNA gene solution from running radiallyfrom one spot to another as defined by the barrier means.
 26. The dryDNA transfer media as claimed in claim 25 , wherein said media is paper,and wherein said barriers comprises mechanical indentions sized to andconfigured to said wells at respective well locations.
 27. The dry DNAtransfer media as claimed in claim 25 , wherein said media comprises acomposite structure including a non-porous sheet bearing spaced cutoutscorresponding to said well openings at respective locationscorresponding to said wells and carrying coplanar porous inserts withinrespective cutouts.
 28. The dry DNA transfer media as claimed in claim27 , wherein said inserts are formed of porous paper.